Atorvastatin Treatment of Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial PROJECT SUMMARY More than a million Americans harbor a cerebral cavernous angioma (CA). Of particular concern is the exceptionally high bleeding risk in the fewer than 200,000 cases who have suffered a recent symptomatic hemorrhage, and the high cost and morbidity of stroke and potential surgical interventions in this setting. It would be desirable to develop a drug that stabilizes the hemorrhagic CA lesion and lessen the burden of re- bleeding. A decade of research has identified RhoA kinase (ROCK) activation as a signaling aberration mediating vascular hyper-permeability and bleeding in CAs. ROCK inhibition therapy has been shown to blunt of CA lesion development and hemorrhage in mouse models recapitulating the human disease. A similarly robust therapeutic benefit was recently documented with the hydroxy-methylglutaryl-coenzyme-A reductase inhibitor atorvastatin, and a demonstrably weaker effect by lower potency simvastatin. Atorvastatin, in wide clinical use, achieves ROCK inhibition pleiotropic effect in humans, at approved and well tolerated doses. The Chicago team has implemented and validated novel magnetic resonance imaging techniques in CA patients, reflecting lesional hemorrhage (quantitative susceptibility mapping, QSM) and vascular permeability (dynamic contrast enhanced quantitative perfusion, DCEQP), and linked these measures to clinical hemorrhage in human subjects. These discoveries have motivated a prospective, randomized, double-blinded, placebo- controlled, Phase I-IIa exploratory proof of concept trial assessing the effects of atorvastatin, at doses shown to cause ROCK inhibition, on CA lesions that have recently bled. The primary objective shall evaluate whether the treatment produces a difference in lesional iron deposition (QSM biomarker activity) compared to placebo. Secondary aims shall assess the drug effects on a second biomarker (DCEQP vascular permeability), link drug treatment to ROCK activity in peripheral leukocytes, examine signal effects on clinical outcomes and adverse events, and query pre-specified subgroups. Accounting for all causes of potential attrition and missing data, the study is powered to test the primary hypothesis by enrolling 80 subjects (40 each in placebo and atorvastatin groups). Subjects will be followed for 2 years, with plans for futility analysis and adaptive change in sample size based on observed biomarker effects at midpoint of the trial. This is the first therapeutic trial focused on stabilizing a CA that had recently bled, using mechanistically targeted vascular permeability therapy with the goal of lessening re-bleeding. It will answer the urgent call by the clinical and patient community to assess objectively and scientifically whether the widely available (and in some ways seductive) statins may have a role in CA therapy. A team of investigators and consultants and a robust trial readiness infrastructure have been assembled to maximize the rigor of the proposed study and insure its successful execution. Implications of positive and negative trial results are presented, and corollary go-no-go propositions, within the scope of a broader therapeutic development roadmap. This trial has received U.S. F.D.A. IND Exemption #126840.